Transmission of Hepatitis C Virus (HCV) from patients to health care workers (HCW) through needlestick events is a significant and underappreciated problem. In an NIH funded R03 Pilot Study, we have observed that 6.6 percent of health care workers exposed through needlestick to blood from HCV positive patients acquired infection; this observation is in keeping with a previous report of 10 percent transmission when source patients were documented to be viremic. As prevalence rates of HCV infection among hospitalized patients rise, particularly in urban settings such as ours, this problem will increase in magnitude. For instance, among the coalition of Baltimore hospitals collaborating in this proposal, more than 150 needlestick exposures to HCV were reported by health care workers during the past year. Furthermore, we are aware of at least 5 episodes of HCV transmission occurring in those same hospitals over the past year. To address this problem, we will perform a multicenter prospective observational trial of needlestick events occurring at hospitals in Baltimore. We will define the risk of HCV transmission through high-risk needlestick events, and determine the influence of source patient virus characteristics and HCV-specific antibody responses on viral transmission. Exposed HCWs will be enrolled at the time of exposure, and followed through twelve months. Serum and peripheral blood mononuclear cells will be collected at baseline, and at 2, 4, 6, 8, 12, 24 and 52 weeks following exposure, for detailed virologic and immunologic analyses. Source patient HCV will also be characterized, including viral titer and genotype, quasispecies diversity, and antibody binding. To examine the hypothesis that neutralizing antibody in source patient sera may protect against transmission, we will assay source sera for anti-E2 antibodies (NOB less than neutralization of binding greater than assay). Through these investigations, we will gain insight into the risk factors for transmission, and factors associated with protection from transmission. We will characterize immunologic and virologic events occurring in response to acute HCV infection. Peripheral blood CD4 proliferative responses to immunodominant T cell epitopes; peripheral blood CTL responses to specific peptide; and cultured lymphocyte cytokine response profiles (Th1/Th2/Th0) will be measured in blood samples collected through the earliest stages of infection. HCV-E2 specific antibody responses will measured over time, examined in light of of viral quasispecies evolution, and correlated with outcome of infection. We will explore the tropism of HCV for peripheral blood mononuclear cell populations through the course of early infection, to determine the influence of host antibody on viral/cell interactions. Through the creation of the coalition of participating hospitals, in a synergistic collaboration with front-line employee health practitioners across the city, we will better define the risk of HCV transmission, define early events in acute HCV infection, and create a platform from which prophylactic interventions may be evaluated in the future.